Prodrugs

Question 1

what is a prodrug

Answer 1

biologically inactive molecule
- metabolised to produce the active drug

Question 2

why are prodrugs needed

Answer 2

1. pharmacodynamics
   - reduce toxicity or adverse events
2. pharmacokinetics
   - improve absorption
   - reduce first pass metabolism
   - improve duration of action
   - site specific targeting
3. pharmaceutical
   - solubility
   - stability
   - acceptability

Question 3

what are the classifications of prodrugs by objectives

Answer 3

1. exploiting transport mechanisms- site specific targeting
2. reducing toxicity
3. improved absorption/penetration
4. improved chemical stability
5. modified duration of action
6. improved aqueous solubility
7. improved patient acceptability

Question 4

give an example of a prodrug exploiting transport mechanisms

Answer 4

gabapentin enacarbil for epilepsy and neuropathic pain
- substrate for monocarboxylic acid transporter and sodium dependent multivitamin transporter
- has better oral bioavailability than gabapentin

Question 5

give an example of a prodrug activating site specific targeting

Answer 5

1. conjugation to antibodies
2. many tumours over express receptors or carriers
   - transferrin
   - epidermal growth factors
3. intramolecular rearrangement
4. allows for site specific delivery of drugs
5. reduces toxicity to other organs

Question 6

give an example of a prodrug reducing toxicity

Answer 6

1. cyclophosphamide
   - alkylating agent
   - non toxic until activated intracellularly
2. sulindac- NSAID
   - sulfoxide is reduced to a sulfide in liver
   - has reduced GIT irritation

Question 7

give an example of how a prodrug improves absorption/penetration

Answer 7

1. increases lipophilicity
2. reduce polar surface area
   - eg. losartan in GIT
   - angII antagonist
   - activated by CYP2C9
   - hydroxy group on imidazole oxidised to COOH

Question 8

give examples of prodrugs that improve chemical stability

Answer 8

• erythromycin
• resistant to gastric acid and masks bitter taste

Question 9

give an example of a prodrug which modified duration of action

Answer 9

chloramphenicol
- fatty acid ester makes it water insoluble
- increases duration of action

Question 10

how is aqueous solubility improved

Answer 10

introduce an ionisable group
- succinate
- phosphate
- sulfate esters

Question 11

give an example of a prodrug with improved aqueous solubility

Answer 11

fosphenytoin sodium
- water soluble prodrug of phenytoin
- improves formulation challenges of phenytoin

Question 12

how can acceptability be improved

Answer 12

modifying taste
- eg. erythromycin, chloramphenicol